POS1128 ZETOMIPZOMIB (KZR-616) TREATMENT RESULTS IN CLINICALLY MEANINGFUL RENAL RESPONSES IN PATIENTS WITH LUPUS NEPHRITIS
Authors: A. Saxena, S. Parikh, S. Hua, R. Leff, E. Park, N. Henig
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Zetomipzomib, a first-in-class selective inhibitor of the immunoproteasome blocks multiple pathways involved in inflammatory cytokine production and immune effector cell activity – including macrophages, B cells and T cells leading to broad immunomodulation across both the innate and adaptive immune systems<sup>[1-3]</sup>. The MISSION Phase 1b/2, open-label study (NCT03393013; KZR-616-002) evaluated safety, tolerability, and exploratory efficacy of zetomipzomib in patients with systemic lupus erythematosus (SLE) +/- lupus nephritis (LN). In the Phase 1b portion, zetomipzomib was well-tolerated in patients with active SLE +/- LN and resulted in improvement across disease activity measures as well as biomarkers, including reduced proteinuria and urinary CD163 in 2 of 2 patients with LN<sup>[4]</sup>. <h3>Objectives</h3> Results from the completed Phase 2 portion of the MISSION study are presented here. <h3>Methods</h3> MISSION Phase 2 evaluated zetomipzomib 60 mg SC QW in patients with active LN (Class III or IV ± Class V) with proteinuria, defined as urine protein to creatinine ratio (UPCR) &gt;1 despite stable background therapy of ≥8 weeks. Patients received zetomipzomib for 24 weeks. Safety, tolerability, UPCR, other measures of renal function, SLE disease activity, and biomarkers were measured. <h3>Results</h3> 21 patients received ≥1 dose of zetomipzomib (safety population) and 4 patients discontinued before end of treatment (evaluable population, n=17). 90.5% were women with a mean age of 35.3 years; 52.4% were Hispanic/Latino. Patients had mean LN duration of 5.3 years with mean 24-hour UPCR of 2.6 mg/mg and mean eGFR of 104.7 mL/min/1.73 m<sup>2</sup>. Concomitant medications included corticosteroids (100%, mean dose: 20.2 mg/d), MMF or mycophenolic acid (95.2%), HCQ (66.7%), and/or AZA (9.5%). Clinically meaningful renal responses were observed by the end of treatment (EOT) at Week (W) 25 with 11/17 evaluable patients demonstrating ≥50% reduction in UPCR from baseline and 6 of 17 patients achieving a Complete Renal Response*. Furthermore, renal responses were maintained or deepened through the end of study 12-weeks post-treatment at W37. eGFR levels remained stable throughout the study. Reduction of daily steroid dose to 10 mg/day was observed in 14/17 patients as early as W13 and at W25 while other background immunosuppressive doses remained stable throughout the study. Urinary CD163, a marker of inflammation, decreased with zetomipzomib treatment and was shown to be correlated with UPCR. Adverse events were generally mild to moderate (Grade 1/2) without evidence of immunosuppression (no serious/opportunistic infections or immune cell depletion). *Complete Renal Response: UPCR ≤0.5, eGFR ≥60 mL/min/1.73m<sup>2</sup> or no worsening of eGFR from baseline of ≥25%, prednisone (or equivalent) ≤10 mg and no use of prohibited medication. <h3>Conclusion</h3> In the MISSION Phase 2 study, treatment with zetomipzomib 60 mg SC QW for 24 weeks demonstrated strong activity against LN as evidenced by improvement in UPCR and has the potential to be a long-term, steroid-sparing immunomodulatory treatment for LN patients. <h3>References</h3> [<b>1]</b> Muchamuel et al. <i>Nat Med</i>. 2009;15(7):781-7. [<b>2]</b> Ichikawa et al. <i>Arthritis Rheum</i>. 2012;64(2):493-503. [<b>3]</b> Kalim et al. <i>J Immunol</i>. 2012;189(8):4182-93. [<b>4]</b> Furie et al. EULAR 2021 Virtual Congress. [<b>5]</b> Mejia-ViletJ, et al. <i>JASN</i>. 2020;31(6):1335-1347. <h3>Acknowledgements</h3> Submitted on behalf of the MISSION (KZR-616-002) Phase 2 Investigators. <h3>Disclosure of Interests</h3> Amit Saxena Consultant of: AstraZeneca, BMS, Eli Lilly, GSK, Kezar Life Sciences, SV Parikh Consultant of: Alexion, Aurinia, BMS, GSK, Kezar Life Sciences, Grant/research support from: Aurinia, EMD-Serono, NIH-NIDDK, Steven Hua Shareholder of: Kezar Life Sciences, Employee of: Kezar Life Sciences, Richard Leff Shareholder of: Kezar Life Sciences, Consultant of: Kezar Life Sciences, Eunmi Park Shareholder of: Kezar Life Sciences, Employee of: Kezar Life Sciences, Noreen Henig Shareholder of: Kezar Life Sciences, Employee of: Kezar Life Sciences.